Benzodiazepines are among the most frequently prescribed medications in the United States and internationally. Tolerance develops commonly to these drugs, limiting their use in some clinical situations, and requiring increased doses with increased side effects in other cases. In addition, a characteristic withdrawal syndrome occurring after termination of chronic benzodiazepine use is compatible with physiological dependence on these drugs. Dependence may in turn contribute to abuse of benzodiazepines. Although tolerance and withdrawal have been reproduced in animal models, the mechanisms of tolerance and dependence to benzodiazepines remain uncertain. This proposal is designed to assess the behavioral and neurochemical correlates of benzodiazepine tolerance and dependence. Preliminary data from our studies of chronic lorazepam treatment indicate that tolerance develops rapidly to this drug, that plasma and brain concentrations remain constant, and that decreases in benzodiazepine receptor binding in several brain regions closely parallel the time course for the development of tolerance. After drug discontinuation, tolerance and decreased receptor binding persist for several days, followed by increases in receptor binding prior to a return to control values. These findings suggest that changes in receptor binding may contribute to benzodiazepine tolerance and withdrawal. We propose to extend these studies to other benzodiazepines, including agonists (clonazepam, alprazolam, and triazolam), an antagonist (Ro15-1788) and an inverse agonist (FG 7142), and to assess several major determinants of drug effect: behavior, including ataxia and operant performance; plasma and brain drug concentrations; and receptor binding and function, including the major binding sites and ion flux. Combination of these approaches will provide a unique and comprehensive picture of benzodiazepine tolerance and dependence.